PRODUCT MONOGRAPH - Home | UCB (lacosamide) Page 1 of 36 PRODUCT MONOGRAPH PrVIMPAT® lacosamide 50 mg, 100 mg, 150 mg and 200 mg film-coated tablets and 10 mg/mL solution for injection

VIMPAT (lacosamide) Page 1 of 36

PRODUCT MONOGRAPH

PrVIMPAT®

lacosamide

50 mg, 100 mg, 150 mg and 200 mg film-coated tablets and 10 mg/mL solution for injection

Antiepileptic Agent

UCB Canada Inc. Oakville, ON L6H 5R7

Date of Preparation: February 22, 2013

Control Number: 160660 ® Registered trademark used under license from Harris FRC Corporation


Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3 SUMMARY PRODUCT INFORMATION ........................................................................3 INDICATIONS AND CLINICAL USE ..............................................................................3 CONTRAINDICATIONS ...................................................................................................4 WARNINGS AND PRECAUTIONS ..................................................................................4 ADVERSE REACTIONS ....................................................................................................9 DRUG INTERACTIONS ..................................................................................................17 DOSAGE AND ADMINISTRATION ..............................................................................19 OVERDOSAGE ................................................................................................................21 ACTION AND CLINICAL PHARMACOLOGY ............................................................22 STORAGE AND STABILITY ..........................................................................................25 DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................26

PART II: SCIENTIFIC INFORMATION ...............................................................................28 PHARMACEUTICAL INFORMATION ..........................................................................28 CLINICAL TRIALS ..........................................................................................................28 DETAILED PHARMACOLOGY .....................................................................................30 TOXICOLOGY .................................................................................................................31 REFERENCES ..................................................................................................................33

PART III: CONSUMER INFORMATION ..............................................................................34


PrVIMPAT®

lacosamide

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Nonmedicinal Ingredients

Oral Film-coated tablets / 50 mg, 100 mg, 150 mg and 200 mg

colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments: 50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake 100 mg tablets: yellow iron oxide 150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake

Intravenous Solution for injection / 10 mg/mL

hydrochloric acid, sodium chloride, water for injection

INDICATIONS AND CLINICAL USE Adults (18 years of age) VIMPAT (lacosamide) is indicated as adjunctive therapy in the management of partial-onset seizures in adult patients with epilepsy who are not satisfactorily controlled with conventional therapy. VIMPAT (lacosamide) solution for injection for intravenous use is an alternative when oral administration is temporarily not feasible. Geriatrics ( 65 years of age) The clinical experience with VIMPAT in elderly patients with epilepsy is limited (n=18). Caution should be exercised during dose titration and age-associated decreased renal clearance should be considered in elderly patients (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics, DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics).


Pediatrics (<18 years of age) The safety and efficacy of VIMPAT in pediatric patients (<18 years of age) have not been established and its use in this patient population is not indicated (see WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics). Only ten pediatric patients (16 to 17 years of age) participated in controlled trials of partial-onset seizures. CONTRAINDICATIONS

Patients who are hypersensitive to the active substance or to any of the excipients. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the product monograph.

Patients with a history of, or presence of, second- or third-degree atrioventricular (AV)

block. WARNINGS AND PRECAUTIONS General Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, VIMPAT (lacosamide) should be withdrawn gradually (over a minimum of 1 week) to minimize the potential of increased seizure frequency (see DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment). Cardiac Rhythm and Conduction Abnormalities PR Interval Prolongation Second degree or higher AV block has been reported in post-marketing experience. Patients should be made aware of the symptoms of second-degree or higher AV block (e.g. slow or irregular pulse, feeling of lightheadedness and fainting), and told to contact their physician should any of these symptoms occur. VIMPAT should be used with caution in patients with known conduction problems [e.g. marked first-degree atrioventricular (AV) block, sick sinus syndrome without pacemaker], or with a history of severe cardiac disease such as myocardial ischemia or heart failure. In such patients, obtaining an ECG before beginning VIMPAT, and after VIMPAT is titrated to steady-state, is recommended. Caution should especially be exerted when treating elderly patients as they may be at increased risk of cardiac disorder or when VIMPAT is given with other drugs that prolong the PR interval (e.g. carbamazepine, pregabalin, lamotrigine or beta-blockers), as further PR prolongation is possible (see DRUG INTERACTIONS). In clinical trials of healthy subjects and patients with epilepsy, VIMPAT treatment was associated with PR interval prolongation in a dose-dependent manner (see ACTION AND


CLINICAL PHARMACOLOGY, Pharmacodynamics). Patients with significant electrocardiographic (ECG) abnormalities were systematically excluded from these trials. The mean PR interval increase (at tmax) in a clinical pharmacology ECG trial of healthy subjects was 13.6ms for the 400mg/day VIMPAT group, 18.2ms for the 800mg/day VIMPAT group, and 6.3ms for the placebo group. The mean increase in PR interval at the end of 12 weeks maintenance treatment for patients with partial-onset seizures who participated in the controlled trials was 1.4ms, 4.4ms, and 6.6ms for the VIMPAT 200, 400, and 600mg/day groups, respectively, and -0.3ms for the placebo group. The mean maximum increase in PR interval in these controlled trials was 12.7ms, 14.3ms, and 15.7ms in the VIMPAT 200, 400, and 600mg/day groups and 11.2ms in the placebo group. Among patients who participated in these controlled trials, asymptomatic first-degree atrioventricular (AV) block was detected on ECG and reported as an adverse reaction for 0.4% (4/944 patients ) in the VIMPAT group and 0% (0/364 patients) in the placebo group (see ADVERSE REACTIONS). Atrial Fibrillation and Atrial Flutter VIMPAT administration may predispose to atrial arrhythmias (atrial fibrillation or flutter), especially in patients with diabetic neuropathy and/or cardiovascular disease. Patients should be made aware of the symptoms of atrial fibrillation and flutter (e.g. palpitations, rapid or irregular pulse, shortness of breath) and told to contact their physician should any of these symptoms occur. Atrial fibrillation and flutter have been reported in open-label epilepsy trials and in post-marketing experience. No cases occurred in the short-term investigational trials of VIMPAT in epilepsy patients. In patients with diabetic neuropathy, 0.6% of patients treated with VIMPAT experienced an adverse reaction of atrial fibrillation or atrial flutter, compared to 0% of placebo-treated patients. Syncope In the short-term controlled trials of VIMPAT in epilepsy patients with no significant system illnesses, there was no increase in syncope compared to placebo. In the short-term controlled trials of VIMPAT in patients with diabetic neuropathy, 1.0% of patients who were treated with VIMPAT reported an adverse reaction of syncope or loss of consciousness, compared to 0% of placebo-treated patients with diabetic neuropathy. Most of the cases of syncope were observed in patients receiving doses above 400 mg/day. The cause of syncope was not determined in most cases. However, several were associated with either changes in orthostatic blood pressure, atrial flutter/fibrillation (and associated tachycardia), or bradycardia (see ADVERSE REACTIONS, Intravenous Adverse Reactions). Carcinogenesis and Mutagenesis See Product Monograph Part II: TOXICOLOGY, Carcinogenicity and Mutagenicity for discussion on animal data. Hypersensitivity Multiorgan hypersensitivity reactions (including Drug Rash with Eosinophilia and Systemic Symptoms, or DRESS), Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis


(TEN) have been reported with anticonvulsants. Typically, although not exclusively, DRESS presents with fever and rash associated with other organ system involvement, that may or may not include eosinophilia, hepatitis, nephritis, lymphadenopathy, and/or myocarditis. Because these disorders are variable in their expression, other organ system signs and symptoms not noted here may also occur. If any of these hypersensitivity reactions are suspected, VIMPAT should be discontinued and alternative treatment started. One case of symptomatic hepatitis and nephritis was observed among 4011 subjects exposed to VIMPAT during clinical development. The event occurred in a healthy volunteer, 10 days after stopping VIMPAT treatment. The subject was not taking any concomitant medication and potential known viral etiologies for hepatitis were ruled out. The subject fully recovered within a month, without specific treatment. The case is consistent with a delayed multiorgan hypersensitivity reaction. Additional potential cases included 2 with rash and elevated liver enzymes and 1 with myocarditis and hepatitis of uncertain etiology. SJS has been reported very rarely in post-marketing experience during treatment with VIMPAT in combination with other antiepileptic drugs. A causal relationship between SJS and VIMPAT treatment has not been established. SJS was not reported during clinical development. No cases of TEN were reported during clinical development. One case of TEN has been reported in post-marketing experience during treatment with VIMPAT in combination with other drugs, including another antiepileptic drug. A causal relationship between TEN and VIMPAT treatment has not been established. Neurologic Dizziness and Ataxia Treatment with VIMPAT has been associated with dizziness and ataxia which could increase the occurrence of accidental injury or falls. In controlled clinical trials, dizziness was experienced by 25% of patients with partial-onset seizures taking 1 to 3 concomitant AEDs randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared with 8% of placebo patients) and was the adverse event most frequently leading to discontinuation (3%). Ataxia was experienced by 6% of patients randomized to the recommended doses (200 to 400 mg/day) of VIMPAT (compared to 2% of placebo patients) (see ADVERSE REACTIONS, Clinical Trial Adverse Drug Reactions). There was a substantial increase in the frequency of occurrence of these events when patients received VIMPAT doses greater than 400 mg/day. Accordingly, patients should be advised not to drive a car or to operate other complex machinery or perform hazardous tasks until they are familiar with the effects of VIMPAT on their ability to perform such activities (see Part III: CONSUMER INFORMATION).


Ophthalmological Effects In controlled trials in patients with partial-onset seizures, VIMPAT treatment was associated with vision-related adverse events such as blurred vision (VIMPAT, 8%; placebo, 3%) and diplopia (VIMPAT, 11%; placebo, 2%). Three percent of patients randomized to VIMPAT discontinued treatment due to vision-related adverse events (primarily diplopia) (see ADVERSE REACTIONS). Patients should be informed that if visual disturbances occur, they should notify their physician promptly. If visual disturbance persists, further assessment, including dose reduction and possible discontinuation of VIMPAT, should be considered. More frequent assessments should be considered for patients with known vision-related issues or those who are already routinely monitored for ocular conditions. Psychiatric Suicidal Ideation and Behaviour Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge. An FDA meta-analysis of randomized placebo controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs. The mechanism of this risk is not known. There were 43892 patients treated in the placebo controlled clinical trials that were included in the meta-analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy. Patients with epilepsy represented approximately 25% of the total number of patients treated in the placebo controlled clinical trials and, for the majority of epilepsy patients, treatment (antiepileptic drug or placebo) was administered as adjunct to other antiepileptic agents (i.e., patients in both treatment arms were being treated with one or more antiepileptic drug). Therefore, the small increased risk of suicidal ideation and behaviour reported from the meta-analysis (0.43% for patients on antiepileptic drugs compared to 0.24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications. The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug-placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.


Special Populations Women of Childbearing Potential / Contraception: There was no clinically relevant interaction between lacosamide and oral contraceptives (ethinylestradiol and levonorgestrel) in clinical studies (see DRUG INTERACTIONS, Drug-Drug Interactions, Oral Contraceptives). Pregnant Women: There are no studies with lacosamide in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats and rabbits at maternal toxic doses (see TOXICOLOGY, Reproduction Studies). Since the potential risk for humans is unknown, VIMPAT should not be used during pregnancy unless the benefit to the mother clearly outweighs the potential risk to the foetus. If women decide to become pregnant while taking VIMPAT, the use of this product should be carefully re-evaluated. Pregnancy Registry: Physicians are advised to recommend that pregnant patients taking VIMPAT enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the following website: http://www.aedpregnancyregistry.org/ Nursing Women: It is unknown whether lacosamide is excreted in human breast milk. Animal studies have shown excretion of lacosamide in breast milk. Because many drugs are excreted into human milk, a decision should be made whether to discontinue nursing or to discontinue lacosamide, taking into account the importance of the drug to the mother. Fertility: No adverse effects on male or female fertility or reproduction were observed in rats at doses producing plasma exposures (AUC) up to approximately 2 times the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day. Geriatrics (≥ 65 years of age): The experience with VIMPAT in elderly patients with epilepsy is limited (n = 18). Although no dose reduction is necessary in elderly patients, caution should be exercised during dose titration and age-associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics). Pediatrics (< 18 years of age): VIMPAT is not indicated for use in pediatrics (< 18 years of age) as there is insufficient data on safety and efficacy of the drug in this population (see INDICATIONS and DOSAGE AND ADMINISTRATION). Monitoring and Laboratory Tests See WARNINGS AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities.


ADVERSE REACTIONS Adverse Drug Reaction Overview In controlled clinical trials in patients with partial-onset seizures, 924 patients received VIMPAT (lacosamide). Some of the most frequently reported adverse reactions in controlled clinical trials with lacosamide treatment were dizziness, nausea, and vision-related events (e.g. diplopia, blurred vision). They were dose-related and usually mild to moderate in intensity. Clinical Trial Adverse Drug Reactions Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 1 gives the incidence of treatment-emergent adverse events that occurred in ≥1% of adult patients with partial-onset seizures in the total VIMPAT group (n=944) and for which the frequency was greater than placebo, in controlled clinical trials. The majority of adverse events were reported with a maximum intensity of ‘mild’ or ‘moderate’.


Table 1: Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled Partial-Onset Seizure Trials (Events ≥1% of Patients in the total VIMPAT group and More Frequent Than in the Placebo Group).

MedDRA

System Organ Class/ Preferred Term

Placebo N=364

%

200 mg/day N=270

%

400 mg/day N=471

%

600 mg/day N=203

%

Ear and labyrinth disorders

Vertigo 1 5 3 4

Tinnitus 1 0 2 2

Eye disorders

Diplopia 2 6 10 16

Vision blurred 3 2 9 16

Conjunctivitis <1 2 <1 0

Gastrointestinal disorders

Nausea 4 7 11 17

Vomiting 3 6 9 16

Diarrhoea 3 3 5 4

Constipation 1 1 2 4

Flatulence 0 3 2 1

Dyspepsia 1 1 2 2

Toothache 1 2 2 1

Dry Mouth 1 1 1 2

Hypoaesthesia oral 0 0 1 1

General disorders and administration site conditions

Fatigue 6 7 7 15

Gait disturbance <1 <1 2 4

Asthenia 1 2 2 4

Irritability 1 1 2 2

Chest pain 1 2 1 2

Pyrexia 1 2 1 1

Feeling drunk 0 0 1 3

Oedema peripheral 0 1 <1 2

Feeling abnormal <1 0 1 2

Infections and infestations

Nasopharyngitis 6 6 8 4


Bronchitis 0 2 1 1

Rhinitis <1 <1 1 1

Ear infection <1 1 1 0

Cystitis <1 1 <1 1

Gastroenteritis 0 1 <1 0

Injury, poisoning and procedural complications

Contusion 3 3 4 2

Skin laceration 2 2 3 3

Fall <1 1 2 1

Head injury <1 2 1 1

Joint sprain 0 1 1 2

Investigations

Positive rombergism 0 1 1 2

Gamma-glutamyltransferase increased

<1 2 <1 1

White blood cell count decreased

<1 0 <1 2

Metabolism and nutrition disorders

Decreased appetite <1 <1 2 3

Hypercholesterolaemia <1 1 1 1

Musculoskeletal and connective tissue disorders

Muscle spasms <1 1 1 2

Neck pain <1 1 1 1

Nervous system disorders

Dizziness 8 16 30 53

Headache 9 11 14 12

Ataxia 2 4 7 15

Somnolence 5 5 8 8

Tremor 4 4 6 12

Nystagmus 4 2 5 10

Balance disorder 0 1 5 6

Memory Impairment 2 1 2 6

Cognitive disorder <1 <1 2 2

Hypoaesthesia 1 2 2 2

Dysarthria <1 <1 1 3


Disturbance in attention 1 0 1 2

Psychiatric disorders

Depression 1 2 2 2

Insomnia 1 2 2 1

Confusional state 1 0 2 3

Mood altered <1 1 1 2

Respiratory, thoracic and mediastinal disorders

Dyspnoea <1 0 1 1

Epistaxis 0 1 1 0

Skin and subcutaneous tissue disorders

Pruritus 1 3 2 3

Hyperhidrosis <1 0 1 2

Table 2: Incidence of Most Common Dose-Related Treatment-Emergent Adverse Events in Double-Blind, Placebo-Controlled Partial-Onset Seizure Trials (Events ≥1% of Patients in the total VIMPAT group and More Frequent Than in the Placebo Group).

MedDRA

Preferred Term

Placebo N=364

%

200 mg/day N=270

%

400 mg/day N=471

%

600 mg/day N=203

%

Diplopia 2 6 10 16

Vision blurred 3 2 9 16

Nausea 4 7 11 17

Vomiting 3 6 9 16

Dizziness 8 16 30 53

Ataxia 2 4 7 15

Tremor 4 4 6 12

Nystagmus 4 2 5 10

Less Common Clinical Trial Adverse Drug Reactions (<1%): Other adverse events reported by <1% of patients with partial-onset seizures in the total VIMPAT group in placebo-controlled clinical trials that occurred more frequently than in the placebo group were: Eye disorders: eye irritation Nervous system disorders: hypokinesia Vascular disorders: hot flush


Cardiac Dose-dependent prolongations in PR interval with VIMPAT have been observed in clinical studies in patients and in healthy subjects (see ACTION AND CLINICAL PHARMACOLOGY). In clinical trials in patients with partial-onset seizures, asymptomatic first-degree AV block was observed as an adverse reaction in 0.4% (4/944) of patients randomized to receive VIMPAT and 0% (0/364) of patients randomized to receive placebo. In clinical trials in patients with diabetic neuropathy, asymptomatic first-degree AV block was observed as an adverse reaction in 0.6% (8/1393) of patients receiving VIMPAT and 0% (0/470) of patients receiving placebo. No second or higher degree AV block was seen in lacosamide treated epilepsy patients in controlled clinical trials. In clinical trials in patients with diabetic neuropathic pain, second-degree AV block has been rarely reported (<0.1%) (see WARNINGS AND PRECAUTIONS). However, cases with second and third degree AV block associated with lacosamide treatment have been reported in post-marketing experience (see Post-Market Adverse Drug Reactions). Other Adverse Reactions in Patients with Partial-Onset Seizures: The following is a list of treatment-emergent adverse events reported by patients treated with VIMPAT in all clinical trials in patients with partial-onset seizures, including controlled trials and long-term open-label extension trials. Events addressed in other tables or sections are not listed here. Events included in this list from the controlled trials occurred more frequently on drug than on placebo and were based on consideration of VIMPAT pharmacology, frequency above that expected in the population, seriousness, and likelihood of a relationship to VIMPAT. Events are further classified within system organ class. Blood and lymphatic system disorders: neutropenia, anemia Cardiac disorders: palpitations Nervous system disorders: paresthesia, cerebellar syndrome Intravenous Adverse Reactions Adverse reactions with intravenous administration generally appeared similar to those observed with the oral formulation, although intravenous administration was associated with local adverse events such as injection site pain or discomfort (2.5%), irritation (1%), and erythema (0.5%). One case of profound bradycardia (26 bpm: BP 100/60 mmHg) was observed in a patient during a 15 minute infusion of 150 mg VIMPAT. This patient was on a beta-blocker. Infusion was discontinued and the patient recovered. Discontinuation Due to Adverse Events in Pre-marketing Controlled Clinical Studies In controlled clinical trials in patients with partial-onset seizures, the rate of discontinuation as a result of an adverse event was 8% and 17% in patients randomized to receive VIMPAT at doses of 200 and 400 mg/day, respectively (placebo: 5%). At VIMPAT doses of 600 mg/day, 29% of the patients discontinued the trials due to adverse events. The adverse events most commonly (≥1% in the VIMPAT total group and greater than placebo) leading to discontinuation were dizziness, coordination abnormal, vomiting, diplopia, nausea, vertigo, and vision blurred. Other


adverse events that led to discontinuation (<1% in the VIMPAT total group and greater than placebo) were typically CNS related and included tremor, nystagmus, fatigue, balance disorder, and disturbance in attention. Comparison of Gender and Race: The overall adverse event rate was similar in male and female patients. Although there were few non-Caucasian patients, no differences in the incidences of adverse events compared to Caucasian patients were observed. Abnormal Hematologic and Clinical Chemistry Findings: Abnormalities in liver function tests have been observed in controlled trials with VIMPAT in adult patients with partial-onset seizures who were taking 1 to 3 concomitant anti-epileptic drugs. Elevations of ALT to ≥3x ULN (upper limit of normal) occurred in 0.7% (7/935) of VIMPAT patients and 0% (0/356) of placebo patients. One case of hepatitis with transaminases >20x ULN was observed in one healthy subject 10 days after VIMPAT treatment completion, along with nephritis (proteinuria and urine casts). Serologic studies were negative for viral hepatitis. Transaminases returned to normal within one month without specific treatment. At the time of this event, bilirubin was normal. The hepatitis/nephritis was interpreted as a delayed hypersensitivity reaction to VIMPAT. Drug Abuse and Dependence/Liability Lacosamide showed no signs of abuse potential in three rat models. After prolonged administration to rats and dogs, there was no tolerance to lacosamide’s pharmacological actions and abrupt cessation of treatment did not produce symptoms of psychological or physical dependence. In a human abuse potential study, single doses of 200 mg and 800 mg lacosamide produced euphoria-type subjective responses that differentiated statistically from placebo; at 800 mg, these euphoria-type responses were statistically indistinguishable from those produced by alprazolam. The duration of the euphoria-type responses following lacosamide was less than that following alprazolam. A high rate of euphoria was also reported as an adverse event in the human abuse potential study following single doses of 800 mg lacosamide (15% [5/34]) compared to placebo (0%) and in two pharmacokinetic studies following single and multiple doses of 300-800 mg lacosamide (ranging from 6% [2/33] to 25% [3/12]) compared to placebo (0%). However, the rate of euphoria reported as an adverse event in the VIMPAT development program at therapeutic doses was less than 1%. Abrupt termination of lacosamide in clinical trials with diabetic neuropathic pain patients produced no signs or symptoms that are associated with a withdrawal syndrome indicative of physical dependence. However, psychological dependence cannot be excluded due to the ability of lacosamide to produce euphoria-type adverse events in humans.


Post-Market Adverse Drug Reactions Since the first global approval of VIMPAT on 29 August 2008 through 31 August 2012, there are approximately 239, 687 patient-years of exposure to VIMPAT. In addition to the adverse events reported during clinical studies and listed above, the following adverse events have been reported in post-marketing experience. Table 3 is based on post-market spontaneous adverse event reports. The percentages shown are calculated by dividing the number of adverse events reported to the company by the estimated number of patient years exposed to VIMPAT. Because these adverse events are reported spontaneously from a population of uncertain size, it is not possible to reliably estimate their frequency. Furthermore, a causal relationship between VIMPAT and the emergence of these events has not been clearly established.


Table 3: Post-Market Spontaneous Adverse Event Reports Adverse Events Reported Frequency

Uncommon

<1% and ≥0.1%

Rare

<0.1% and ≥0.01%

Very rare <0.01%

Immune system disorders

Drug hypersensitivity reactions

X

Multiorgan hypersensitivity reactions1

X

Blood and lymphatic system disorders

Leukopenia X

Thrombocytopenia X

Agranulocytosis X

Cardiovascular disorders

Bradycardia X

Atrioventricular block X

Atrial fibrillation X

Atrial flutter X

Cardiac arrest X

Cardiac failure X

Myocardial infarction X

Hepatobiliary disorders

Liver function test abnormal X

Metabolism and nutrition disorders

Hyponatremia X

Nervous system disorders

Ataxia X

Syncope X

Psychiatric disorders

Euphoric mood X

Suicide attempt X

Suicidal ideation X

Aggression X

Agitation X

Psychotic disorder X


Insomnia X

Hallucination X

Skin and subcutaneous tissue disorders

Rash X

Angioedema X

Urticaria X

Stevens-Johnson Syndrome X 1 Includes related preferred term DRESS (Drug rash with eosinophilia and systemic syndrome) Cardiac disorders: Second and third degree AV block, and atrial fibrillation and atrial flutter associated with lacosamide treatment have been reported in post-marketing experience (see WARNINGS AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities). DRUG INTERACTIONS VIMPAT (lacosamide) should be used with caution in patients treated with medicinal products known to be associated with PR prolongation (e.g. carbamazepine, lamotrigine, pregabalin, beta-blockers) and in patients treated with class I antiarrhythmic drugs (see WARNINGS AND PRECAUTIONS, Cardiac Rhythm and Conduction Abnormalities).

In Vitro Assessment of Drug Interactions In vitro metabolism studies indicate that lacosamide does not induce the enzyme activity of drug metabolizing cytochrome P450 isoforms CYP1A2, 2B6, 2C9, 2C19 and 3A4 at concentrations (12.5 µg/mL) close to the human peak plasma concentration (10.9 µg/mL, Cmax, steady state at maximum recommended human dose (MRHD) of 400 mg/day). At concentrations 10 times higher (125 µg/mL), enzyme activities were less than 2-fold increased. Lacosamide did not inhibit CYP 1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4/5 at concentrations up to 1000-fold greater than the Cmax for 400 mg/day. The inhibitory concentrations (IC50) of CYP3A4, 3A5, 2C9 and 1A1 by lacosamide are at least 70-fold higher than the Cmax for 400 mg/day.

In vitro data suggest that lacosamide has the potential to inhibit CYP2C19 at therapeutic concentrations (60% inhibition at 25µg/mL). However, an in vivo evaluation in healthy subjects showed no inhibitory effect of lacosamide (600 mg/day administered as 300 mg BID dosing) on the single dose pharmacokinetics of omeprazole (40 mg).

Lacosamide is a CYP2C19 substrate. The relative contribution of other CYP isoforms or non-CYP enzymes in the metabolism of lacosamide is not clear. Lacosamide was not a substrate or inhibitor for P-glycoprotein. Since <15% of lacosamide is bound to plasma proteins, a clinically relevant interaction with other drugs through competition for protein binding sites is unlikely.


In Vivo Assessment of Drug Interactions Drug-drug interaction studies in healthy subjects showed no pharmacokinetic interactions between VIMPAT and carbamazepine, valproic acid, digoxin, metformin, omeprazole, midazolam, or an oral contraceptive containing ethinylestradiol and levonorgestrel. There was no evidence for any relevant drug-drug interaction of VIMPAT with common AEDs in the placebo-controlled clinical trials in patients with partial-onset seizures.

The lack of pharmacokinetic interaction does not rule out the possibility of pharmacodynamic interactions, particularly among drugs that affect the heart conduction system. Drug – Drug Interactions

Drug- Interaction Studies with AEDs: Effect of VIMPAT on concomitant AEDs: VIMPAT 400 mg/day had no influence on the pharmacokinetics of 600 mg/day valproic acid and 400 mg/day carbamazepine in healthy subjects. The placebo-controlled clinical studies in patients with partial-onset seizures showed that steady-state plasma concentrations of levetiracetam, carbamazepine, carbamazepine epoxide, lamotrigine, topiramate, oxcarbazepine monohydroxy derivative (MHD), phenytoin, valproic acid, phenobarbital, gabapentin, clonazepam, and zonisamide were not affected by concomitant intake of VIMPAT at 200 to 600 mg/day. Effect of concomitant AEDs on VIMPAT: Drug-drug interaction studies in healthy subjects showed that 600 mg/day valproic acid had no influence on the pharmacokinetics of 400 mg/day VIMPAT. Likewise, 400 mg/day carbamazepine had no influence on the pharmacokinetics of VIMPAT (400 mg/day) in a healthy subject study. Population pharmacokinetics results in patients with partial-onset seizures showed small reductions (approximately 25% lower) in lacosamide plasma concentrations when VIMPAT (200 to 600 mg/day) was coadministered with carbamazepine, phenobarbital or phenytoin.

Drug-Drug Interaction Studies with Other Drugs: Digoxin VIMPAT (400 mg/day) did not affect pharmacokinetics of digoxin (0.5 mg once daily) in a study in healthy subjects. There was no effect of digoxin on the pharmacokinetics of VIMPAT. Metformin There were no clinically relevant changes in metformin levels following co-administration of VIMPAT (400 mg/day). Metformin (500 mg three times a day) had no effect on the pharmacokinetics of VIMPAT (400 mg/day) in healthy subjects.


Omeprazole Omeprazole is a CYP2C19 substrate and inhibitor. Omeprazole (40 mg once daily) increased the AUC of lacosamide by 19% (300 mg, single dose), which is unlikely to be clinically significant. Lacosamide (600 mg/day) did not affect the single-dose pharmacokinetics of omeprazole (40 mg) in healthy subjects. Midazolam Midazolam is a CYP3A4 substrate. VIMPAT administered as a single 200 mg dose or repeated doses of 400 mg/day (200 mg BID) to healthy subjects had no clinically relevant effect on the AUC of midazolam, but slightly increased the Cmax over time (30% after 13 days). Oral Contraceptives In an interaction trial in healthy subjects, there was no clinically relevant interaction between lacosamide (400 mg/day) and the oral contraceptives ethinylestradiol (0.03 mg) and levonorgestrel (0.15 mg). Progesterone concentrations were not affected when the medicinal products were co-administered (see WARNINGS AND PRECAUTIONS, Women of Childbearing Potential/Contraception). Drug-Food Interactions VIMPAT is completely absorbed after oral administration. Food does not affect the rate or extent of absorption. Drug-Herb Interactions Interactions with herbal products have not been evaluated. Drug-Laboratory Interactions Interactions with laboratory tests have not been observed. DOSAGE AND ADMINISTRATION General Considerations VIMPAT (lacosamide) may be taken with or without food. Film-coated tablets On the first day of treatment the patient starts with VIMPAT 50 mg tablets twice a day. During the second week, the patient takes VIMPAT 100 mg tablets twice a day. Depending on response and tolerability, VIMPAT 150 mg tablets may be taken twice a day during the third week and VIMPAT 200 mg tablets twice a day during the fourth week.


Solution for injection The solution for injection is infused over a period of 30 to 60 minutes twice daily. VIMPAT solution for injection can be administered intravenously (IV) without further dilution. Conversion to or from oral and IV administration can be done directly without titration. The total daily dose and twice daily administration should be maintained. There is experience with twice daily infusions of VIMPAT up to 5 days (n=53). Compatibility and Stability VIMPAT solution for injection can be administered intravenously without further dilution or may be mixed with diluents. VIMPAT solution for injection was found to be physically compatible and chemically stable when mixed with the following diluents for at least 24 hours and stored in glass or polyvinyl chloride (PVC) bags at room temperature 15-30°C. Diluents: Sodium Chloride Injection 0.9% (w/v) Dextrose Injection 5% (w/v) Lactated Ringer's Injection The stability of VIMPAT solution for injection in other infusion solutions has not been evaluated. Product with particulate matter or discoloration should not be used. Any unused portion of VIMPAT solution for injection should be discarded. Do not use if solution shows haziness, particulate matter, discoloration or leakage. Recommended Dose and Dosage Adjustment Adults The recommended starting dose for VIMPAT is 50 mg twice a day, with or without food, which should be increased to an initial therapeutic dose of 100 mg twice a day after one week. Depending on patient response and tolerability, the maintenance dose can be further increased by 50 mg twice a day every week, to a maximum recommended daily dose of 400 mg (200 mg twice a day). Doses above 400 mg/day do not confer additional benefit, are associated with more severe and substantially higher frequency of adverse reactions and are not recommended. In accordance with current clinical practice, if VIMPAT has to be discontinued, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week). VIMPAT therapy can be initiated with either oral or intravenous (IV) administration. Patients with Renal Impairment No dose adjustment is necessary in patients with mild or moderate renal impairment (creatinine clearance (CLCR) >30 mL/min). A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR ≤30 mL/min) and in patients with end-stage renal disease. In all patients with any degree of renal impairment, the dose titration should be performed with


caution (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment). Following a 4-hour hemodialysis treatment, AUC of VIMPAT was reduced by approximately 50%. Thus, dosage supplementation of up to 50% following hemodialysis may be considered. Treatment of patients with end-stage renal disease should be made with caution as there is limited clinical experience in subjects (n=8) and no experience in patients, and there is accumulation of a metabolite (with no known pharmacological activity). Patients with Hepatic Impairment The dose titration should be performed with caution in patients with mild to moderate hepatic impairment. A maximum dose of 300 mg/day is recommended for patients with mild or moderate hepatic impairment. The pharmacokinetics of VIMPAT have not been evaluated in severe hepatic impairment. VIMPAT is not recommended in patients with severe hepatic impairment (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Hepatic Impairment). Geriatrics ( 65 years of age) Clinical experience with VIMPAT in elderly patients with epilepsy is limited (n = 18). Although no dose reduction is necessary in elderly patients, caution should be exercised during dose titration and age-associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients (see ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Geriatrics). Pediatrics (<18 years of age) The safety and effectiveness of VIMPAT in pediatric patients <18 years has not been established, and therefore its use in this patient population is not indicated (see INDICATIONS and WARNINGS AND PRECAUTIONS, Special Populations, Pediatrics). Missed Dose If the patient misses a dose by a few hours, they should be instructed to take VIMPAT as soon as they remember. If it is close to their next dose, they should be instructed to take their medication at the next regular time. Patients should not take two doses at the same time. OVERDOSAGE

Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans There is limited clinical experience with VIMPAT (lacosamide) overdose in humans. Clinical symptoms (dizziness and nausea) following doses of 1200 mg/day were mainly related to the central nervous system and the gastrointestinal system.

For management of a suspected drug overdose, contact your regional Poison Control Centre.


There has been a single case of intentional overdose by a patient who self-administered 12 grams VIMPAT along with large doses of zonisamide, topiramate, and gabapentin. The patient presented in a coma and was hospitalized. An EEG revealed epileptic waveforms. The patient recovered 2 days later. During pre-marketing controlled clinical studies, no intentional overdose of VIMPAT resulted in death. Treatment or Management of Overdose There is no specific antidote for overdose with VIMPAT. Standard decontamination procedures should be followed. General supportive care of the patient is indicated including monitoring of vital signs and observation of the clinical status of patient. A Poison Control Centre should be contacted for up to date information on the management of overdose with VIMPAT. Standard hemodialysis procedures result in significant clearance of VIMPAT (reduction of systemic exposure by 50% in 4 hours). Hemodialysis has not been performed in the few known cases of overdose, but may be helpful based on the patient's clinical state or in patients with significant renal impairment. ACTION AND CLINICAL PHARMACOLOGY Mechanism of Action The precise mechanism by which lacosamide exerts its antiepileptic effect in humans is unknown (see Product Monograph, Part II: DETAILED PHARMACOLOGY, Preclinical Pharmacology, for experimental in vitro and in vivo data in animals). Pharmacodynamics A pharmacokinetic-pharmacodynamic (efficacy) analysis was performed based on the pooled data from the 3 efficacy trials for partial-onset seizures. Lacosamide exposure is correlated with the reduction in seizure frequency. However, in group analyses, doses above 400 mg/day do not appear to confer additional benefit and are associated with more severe and substantially higher frequency of adverse reactions. Cardiac Electrophysiology Electrocardiographic effects of VIMPAT (lacosamide) were determined in a double-blind, randomized clinical pharmacology ECG trial of 247 healthy subjects. Chronic oral doses of 400 and 800 mg/day were compared with placebo and a positive control (400 mg moxifloxacin). VIMPAT did not prolong QTc interval and did not have a dose-related or clinically important effect on QRS duration. VIMPAT produced a dose-related increase in mean PR interval. At steady-state, the time of the maximum observed mean PR interval corresponded with tmax. The placebo-subtracted maximum increase in PR-interval (at tmax) was 7.3 ms for the 400 mg/day group and 11.9 ms for the 800 mg/day group. For patients with partial-onset seizures who participated in the controlled trials, the placebo-subtracted maximum increase in PR interval for a 400 mg/day VIMPAT dose was 3.1 ms. For


patients with diabetic neuropathic pain who participated in controlled trials, the placebo-subtracted maximum increase in PR-interval for a 400 mg/day VIMPAT dose was 8.3 ms (see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS). Pharmacokinetics The pharmacokinetics of VIMPAT has been studied in healthy adult subjects (age range 18 to 87), adults with partial-onset seizures, adults with diabetic neuropathy, and subjects with renal and hepatic impairment. A summary of lacosamide’s pharmacokinetic parameters in healthy subjects is provided in Table 4. Lacosamide is completely absorbed after oral administration with negligible first-pass effect with a high absolute bioavailability of approximately 100%. The maximum lacosamide plasma concentrations occur approximately 0.25 to 4 hours post-dose after oral dosing, and elimination half-life is approximately 13 hours. Steady state plasma concentrations are achieved after 3 days of twice daily repeated administration. Pharmacokinetics of lacosamide is dose proportional (100-800 mg) and time invariant, with low inter- and intra-subject variability. Compared to lacosamide, the major metabolite, O-desmethyl metabolite, has a longer Tmax (0.5 to 12 hours) and elimination half-life (15-23 hours) but has no known pharmacologic activity. Table 4: Summary of Lacosamide’s Pharmacokinetic Parameters in Healthy Subjects

Cmax (µg/mL)

Arithmetic Mean

t1/2 (h)

Arithmetic Mean

AUCT

(µg/mL*h)

Arithmetic Mean

tmax (h)

Median

(range)

Oral Tablet 200mg 5.03 13.96 88.61 0.75

(0.25-4.00)

IV solution for injection 200mg (duration 30 minutes)

5.96 12.00 80.24 0.50

(0.50-2.00)

IV solution for injection 200mg (duration 60 minutes)

5.38 12.00 81.16 1.00

(1.00-3.00)

Absorption: Lacosamide is rapidly and completely absorbed after oral administration. The oral bioavailability of lacosamide tablets is approximately 100%. Following oral administration, the plasma concentration of unchanged lacosamide increases rapidly and reaches Cmax about 0.25 to 4 hours post-dose. Food does not affect the rate and extent of absorption. After intravenous administration (30-60 minutes), Cmax is reached at the end of infusion. The plasma concentration increases proportionally with dose after oral (100-800 mg) and intravenous (50-300 mg) administration. Distribution: The volume of distribution is approximately 0.6 L/kg. Lacosamide is less than 15% bound to plasma proteins.


Metabolism: The metabolism of lacosamide has not been completely characterized. Approximately 95% of the dose is excreted in the urine as drug and metabolites. The major compounds excreted in urine are unchanged lacosamide (approximately 40% of the dose) and its O-desmethyl metabolite, which has no known pharmacological activity (less than 30%). A structurally unknown polar fraction (about 20%) was also found in urine, but was detected only in small amounts (0-2%) in human plasma of some subjects. Small amounts (0.5-2%) of additional metabolites were also found in the urine. The plasma exposure of the major human metabolite (AUC), O-desmethyl-lacosamide, is approximately 15% of the drug product, lacosamide. CYP2C19, CYP2C9 and CYP3A4 are mainly responsible for the formation of the O-desmethyl metabolite. However, no clinically relevant difference in lacosamide exposure was observed comparing its pharmacokinetics in extensive metabolisers (EMs, with a functional CYP2C19) and poor metabolisers (PMs, lacking a functional CYP2C19). Furthermore, an interaction trial with omeprazole (CYP2C19-inhibitor) demonstrated no clinically relevant changes in lacosamide plasma concentrations indicating that the importance of this pathway is minor. No other enzymes have been identified to be involved in the metabolism of lacosamide. Elimination: Lacosamide is primarily eliminated from the systemic circulation by renal excretion and biotransformation. After oral and intravenous administration of 100 mg radiolabeled lacosamide, approximately 95% of radioactivity administered was recovered in the urine and less than 0.5% in the feces. The elimination half-life of the unchanged drug is approximately 13 hours and is not altered by different doses, multiple dosing or intravenous administration. The pharmacokinetics are dose-proportional and time-invariant, with low intra- and inter-subject variability. Following twice daily dosing, steady state plasma concentrations are achieved after a 3 day period. The plasma concentration increases with an accumulation factor of approximately 2. Special Populations and Conditions Geriatrics ( 65 years of age): In a study in elderly men and women, the AUC was about 30 and 50% increased compared to young men, respectively. This is partly related to lower body weight. The body weight normalized difference is 26 and 23%, respectively. An increased variability in exposure was also observed. The renal clearance of lacosamide was only slightly reduced in elderly subjects in this study. Pediatrics (<18 years of age): Pharmacokinetics of lacosamide have not been established in pediatric patients. Gender: VIMPAT clinical trials indicate that gender does not have a clinically relevant influence on the pharmacokinetics of VIMPAT.


Race: Approximately 90% of the patient population in epilepsy trials was Caucasian. There are no clinically relevant differences in the pharmacokinetics of VIMPAT between Asian, Black, and Caucasian subjects. Renal impairment: Lacosamide and its major metabolite are eliminated from the systemic circulation primarily by renal excretion. The AUC of lacosamide was increased approximately 25% in mildly (CLCR 50-80 mL/min) and moderately (CLCR 30-50 mL/min), and 60% in severely (CLCR≤30mL/min) renally impaired patients compared to subjects with normal renal function (CLCR>80mL/min), whereas Cmax was unaffected. No dose adjustment is considered necessary in mildly and moderately renal impaired subjects. A maximum dose of 300 mg/day is recommended for patients with severe renal impairment (CLCR≤30mL/min) and in patients with endstage renal disease. Hemodialysis Lacosamide is effectively removed from plasma by hemodialysis. Following a 4-hour hemodialysis treatment, AUC of VIMPAT is reduced by approximately 50%. Therefore dosage supplementation of up to 50% following hemodialysis should be considered. In all renal impaired patients, the dose titration should be performed with caution. Hepatic impairment: Lacosamide undergoes metabolism. Subjects with moderate hepatic impairment (Child-Pugh B) showed higher plasma concentrations of lacosamide (approximately 50-60% higher AUC compared to healthy subjects). A maximum dose of 300 mg/day is recommended for patients with mild to moderate hepatic impairment. Patients with mild to moderate hepatic impairment should be titrated with caution and observed closely during dose titration. Patients with co-existing hepatic and renal impairment of any degree should also be monitored closely during dose titration. The pharmacokinetics of lacosamide have not been evaluated in patients with severe hepatic impairment. VIMPAT use in patients with severe hepatic impairment is not recommended (see DOSAGE AND ADMINISTRATION and ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Renal Impairment). CYP2C19 Polymorphism: There are no clinically relevant differences in the pharmacokinetics of lacosamide between CYP2C19 poor metabolizers and extensive metabolizers. Results from a trial in poor metabolizers (PM) (N=4) and extensive metabolizers (EM) (N=8) of cytochrome P450 (CYP) 2C19 showed that lacosamide plasma concentrations were similar in PMs and EMs, but plasma concentrations and the amount excreted into urine of the O-desmethyl metabolite were about 70% reduced in PMs compared to EMs. STORAGE AND STABILITY Store at room temperature (15 – 30°C).


DOSAGE FORMS, COMPOSITION AND PACKAGING VIMPAT (lacosamide) tablets VIMPAT film-coated tablets are supplied as follows: 50 mg tablet: VIMPAT tablets 50 mg lacosamide are pink, oval, film-coated tablets debossed with "SP" on one side and "50" on the other. They are supplied in high density polyethylene (HDPE) bottles of 60, 180, 500, and 1000, and as blisters (with polyvinyl chloride (PVC) and polyvinylidene chloride (PVDC) bottom film and aluminum top foil) of 14 tablets. 100 mg tablet: VIMPAT tablets 100 mg lacosamide are dark yellow, oval, film-coated tablets debossed with "SP" on one side and "100" on the other. They are supplied in HDPE bottles of 60, 180, 500, and 1000 and as blisters (with PVC and PVDC bottom film and aluminum top foil) of 14 tablets. 150 mg tablet: VIMPAT tablets 150 mg lacosamide are salmon, oval, film-coated tablets debossed with "SP" on one side and "150" on the other. They are supplied in HDPE bottles of 60, 180, 500, and 1000. 200 mg tablet: VIMPAT tablets 200 mg lacosamide are blue, oval, film-coated tablets debossed with "SP" on one side and "200" on the other. They are supplied in HDPE bottles of 60, 180, 500, and 1000. In addition, a 2 week titration pack containing separate blisters of 50 mg and 100 mg tablets is available. There are 14 tablets of each strength per blister. VIMPAT tablets contain the following nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, and dye pigments as specified below: VIMPAT tablets are supplied as debossed tablets and contain the following coloring agents: 50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake 100 mg tablets: yellow iron oxide 150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake VIMPAT solution for injection VIMPAT solution for injection is a clear, colorless, sterile solution containing 20 mL of 10 mg lacosamide per mL for intravenous infusion. The nonmedicinal ingredients are sodium chloride and water for injection. Hydrochloric acid is used for pH adjustment. VIMPAT solution for injection has a pH of 3.8 to 5.0.


VIMPAT solution for injection 10 mg/mL is supplied in 20 mL colorless single-use glass vials, 10 mg/mL vial.


PART II: SCIENTIFIC INFORMATION PHARMACEUTICAL INFORMATION Drug Substance Common name: lacosamide Chemical name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide (IUPAC) Molecular formula and molecular mass: C13H18N2O3 250.30 Structural formula:

Physicochemical properties: Lacosamide is a white to light yellow powder. It is

sparingly soluble in water and slightly soluble in acetonitrile and ethanol. The melting point of lacosamide is between 140°C and 146°C. The specific optical rotation of lacosamide in methanol at 25°C is between +14 and +18.

CLINICAL TRIALS Study Demographics and Trial Design The efficacy of VIMPAT (lacosamide) as adjunctive therapy in partial-onset seizures was established in three 12-week, randomized, double-blind, placebo-controlled, multicenter trials involving 944 adult patients that were randomized to receive lacosamide (and 364 adult patients that were randomized to placebo). Patients had partial-onset seizures with or without secondary generalization and were not adequately controlled with 1 to 3 concomitant AEDs. During an 8-week baseline period, patients were required to have an average of ≥4 partial-onset seizures per 28 days with no seizure-free period exceeding 21 days. In these 3 trials, patients ranged in age between 16 and 71 years (mean: 38.6 years of age), had a mean duration of epilepsy of 24 years and a median baseline seizure frequency ranging from 10 to 17 per 28 days. A total of 10 patients aged 16 to 17 years were enrolled in the trials. Fifty-one percent of the patients were


female. Overall, 84% of patients were taking 2 to 3 concomitant AEDs. Of these patients, 18% were also receiving concurrent vagal nerve stimulation (VNS). Study 1 compared doses of VIMPAT 200, 400, and 600 mg/day and placebo in 107, 108, 106, and 97 randomized patients, respectively. Study 2 compared doses of VIMPAT 400 and 600 mg/day and placebo in 204, 97, and 104 randomized patients, respectively. Study 3 compared doses of VIMPAT 200 and 400 mg/day and placebo in 163, 159, and 163 randomized patients, respectively. Following the 8-week Baseline Phase, subjects were randomized and up-titrated by initiating treatment at 100 mg/day (50 mg BID), and increased in weekly increments of 100 mg/day to the target dose (a 1-step back-titration of VIMPAT 100 mg/day or placebo was allowed in the case of intolerable adverse events at the end of the Titration Phase). The Titration Phase lasted 6 weeks in Studies 1 and 2, and 4 weeks in Study 3. Following the Titration Phase, patients received a stable dose of VIMPAT for 12 weeks (Maintenance Phase). Among the patients randomized to VIMPAT, 76% completed the Treatment Phase (Titration and Maintenance). The primary efficacy end-point in all three trials was the reduction in seizure frequency per 28 days from Baseline to the Maintenance Phase in VIMPAT arm(s) as compared to placebo. The 50% responder rate (percent of patients with at least 50% reduction in seizure frequency from Baseline to the Maintenance Phase) as compared to placebo was a secondary endpoint. Two trials were conducted in patients with partial-onset seizures using VIMPAT solution for injection. These trials were designed to identify the appropriate infusion duration(s) for VIMPAT solution for injection as a short-term replacement for VIMPAT tablets and to provide data to support the safety of infusion rates including 30 and 60 minutes. A total of 199 patients with partial-onset seizures were exposed to VIMPAT solution for injection. Study results A statistically significant effect (in the reduction of seizure frequency from Baseline to the Maintenance Phase) was observed with VIMPAT doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2). The 50% responder rates for VIMPAT doses of 400 mg and 600 mg/day were also statistically significant compared to placebo (see Table 5).


Table 5: Median Percent Reduction in Partial Seizure Frequency per 28 days and 50% Responder Rates from Baseline to the Maintenance Phase (ITT Population).

AED’s + VIMPAT (mg/day)

Study

Efficacy results

AED’s +

Placebo

200 400 600

1 n Median % Reduction50% Responders

96 10%

21.9%

107 26%

32.7%

107 39%**

41.1%**

105 40%** 38.1%*


104 20.8% 18.3%

-- -- --

201 37.3%** 38.3%**

97 37.8%** 41.2%**


159 20.5% 25.8%

160 35.3%* 35.0%

158 36.4%*

40.5%**

-- -- --

*Significant at the 0.05 level; ** Significant at the 0.01 level. Significance reflects the percent reduction over placebo which is based on log-transformed seizure frequency from pairwise treatment analysis of covariance (ANCOVA) models with terms for treatment, pooled site, and the baseline period measurement and pairwise treatment logistic regression models with terms for treatment and pooled site. A statistically significant reduction in seizure frequency from Baseline to the Treatment Phase (i.e. Titration Phase + Maintenance Phase) was also observed with VIMPAT doses of 200 mg/day (Study 3), 400 mg/day (Studies 1, 2, and 3), and 600 mg/day (Studies 1 and 2) compared to placebo. The 50% responder rates for VIMPAT doses of 400 mg and 600 mg/day were also statistically significant compared to placebo.

There were no significant differences in seizure control as a function of gender. Data on race were limited (8.3% of the patients were non-Caucasian). DETAILED PHARMACOLOGY Preclinical Pharmacology In vitro electrophysiological studies have shown that lacosamide selectively enhances slow inactivation of voltage-gated sodium channels, resulting in reduced hyperexcitability of neuronal membranes and inhibition of repetitive neuronal firing. Lacosamide protected against seizures in a broad range of rodent models (mice and rats) of partial and primary generalized seizures and delayed kindling development. In non-clinical experiments lacosamide in combination with levetiracetam, carbamazepine, phenytoin, valproate, lamotrigine, topiramate or gabapentin showed synergistic or additive anticonvulsant effects. Lacosamide was not effective in the rat WAG/rij model of absence epilepsy and caused mild dose-dependent increases in the number of characteristic EEG spike wave discharges for one hour after single intraperitoneal doses of 3-30 mg/kg. A similar phenomenon also occurs in WAG/rij rats given the other antiepileptic drugs phenytoin and carbamazepine.


A safety pharmacology study with intravenous administration of lacosamide at doses of 2-12 mg/kg in anesthetized beagle dogs showed transient increases in PR interval and QRS complex duration and decreases in blood pressure most likely due to a cardiodepressant action as indicated by decreases in cardiac output. There was evidence of a dose relationship. One high dose dog (12 mg/kg) died due to a marked and sustained drop in blood pressure followed by cardiac arrest. At the low dose, these transient changes started in the same plasma lacosamide concentration range as after maximum recommended clinical dosing (200 mg BID). Progressively reduced systolic, diastolic, and mean arterial blood pressure was also seen in anesthetized Cynomolgus monkeys given up to 4 sequential intravenous lacosamide doses of 15 mg/kg. In anesthetized dogs given intravenous doses of 15-45 mg/kg (given as 1 to 3 sequential doses) and anaesthetized monkeys given intravenous doses of 30-120 mg/kg (given as 1 to 4 sequential doses), slowing of atrial and ventricular conductivity, atrioventricular block and atrioventricular dissociation were seen. In an in vitro assay conducted in HEK293 cells that stably express the human-ether-à-go-go related gene (hERG), a weak 7% inhibition of hERG current was seen only at the highest concentration (3000 μmol/L) tested. This is consistent with the absence of changes in QT interval in safety pharmacology studies conducted in dogs and monkeys. TOXICOLOGY In the toxicity studies, the plasma concentrations of lacosamide obtained were similar or only marginally higher than those observed in patients, which leaves low or non-existing margins to human exposure. Acute Toxicity Results from acute oral dose toxicity studies with lacosamide indicate a no-observed-effect-level (NOEL) of 31.6 mg/kg in both mice and rats. The estimated LD50 values were 383 and 253 mg/kg for mice and rats, respectively. After intravenous administration the NOELs were 10 and 25 mg/kg and the estimated LD50 values were 178 and >100 mg/kg for mice and rats, respectively. In acute toxicity studies, clinical signs at high doses included exaggerated pharmacodynamic effects of lacosamide on the CNS such as reduced motility, ataxia, abdominal/lateral position, loss of righting reflex, reduced muscle tone, hind limb weakness, tremor, dyspnea and convulsions. Long Term Toxicity In repeated oral dose studies, lacosamide caused convulsions in mice, rats, rabbits, and dogs after oral dosing at Cmax exposures generally only slightly higher than the Cmax at steady state of 10.9 μg/mL after the maximum recommended human dose of 200 mg BID in patients. The Cmax ratios were as low as 4.1 in mice, 1.6 in rats, 2.3 in rabbits, and 1.8 in adult and juvenile dogs at the lowest dose causing convulsions and as low as 2.7 in mice, less than 1.6 in rats, 1.2 in rabbits, 1.3 in adult dogs, and 0.8 in juvenile dogs at the highest dose level not associated with convulsions. The convulsions usually occurred in the context of other significant clinical signs including one or more of tremors, ataxia, hypoactivity, and recumbency, which also occurred at dose levels not associated with convulsions.


Consistent with the safety pharmacology studies, lacosamide caused 13%-37% decreases in systolic blood pressure in females in the 12 month chronic dog toxicity study at dose levels of 10-25 mg/kg/day with the Cmax at 10 mg/kg similar to that of humans given the maximum recommended dose of 200 mg BID. In the repeated dose toxicity studies, mild reversible liver changes were observed in rats starting at about 3 times the clinical exposure. These changes included an increased organ weight, hypertrophy of hepatocytes, increases in serum concentrations of liver enzymes and increases in total cholesterol and triglycerides. Apart from the hypertrophy of hepatocytes, no other histopathologic changes were observed. Reproduction Studies In reproductive and developmental toxicity studies in rodents and rabbits, no teratogenic effects but an increase in numbers of stillborn pups and pup deaths in the peripartum period, and slightly reduced live litter sizes and pup body weights were observed at maternal toxic doses in rats corresponding to clinically relevant plasma exposure levels. Since higher exposure levels could not be tested in animals due to maternal toxicity, data are insufficient to fully characterize the embryofetotoxic and teratogenic potential of lacosamide. Studies in pregnant rats revealed that lacosamide and/or its metabolites readily crossed the placental barrier. Oral administration of lacosamide (30, 90, or 180 mg/kg/day) to rats during the neonatal and juvenile periods of postnatal development resulted in decreased brain weights and long-term neurobehavioral changes (altered open field performance, deficits in learning and memory). The relevance of these observations remains equivocal. However, potential adverse effects on CNS development cannot be ruled out. The early postnatal period in rats is generally thought to correspond to late pregnancy in humans in terms of brain development. The no-effect dose for developmental neurotoxicity in rats was associated with a plasma lacosamide AUC approximately 0.5 times that in humans at the MRHD of 400 mg/day. Carcinogenicity There was no evidence of drug related carcinogenicity in mice or rats. Mice and rats received lacosamide once daily by oral administration for 104 weeks at doses producing plasma exposures (AUC) up to approximately 1 and 3 times, respectively, the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day. Mutagenicity Lacosamide was negative in an in vitro Ames test and an in vivo mouse micronucleus assay and an in vivo unscheduled DNA synthesis (UDS) test. In the in vivo tests, plasma exposures (AUC) correspond to up to approximately 3 times the plasma AUC in humans at the maximum recommended human dose (MRHD) of 400 mg/day. Lacosamide induced a positive response in the in vitro mouse lymphoma assay at excessively high concentrations (i.e. at concentrations above the maximum recommended concentration of 10 mM).


REFERENCES Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia 2007; 1-10 48(7): 1308-1317. (Study 1) Ben-Menachem E. Lacosamide: An investigational drug for adjunctive treatment of partial-onset seizures. Drugs of Today 2008, 44 (1): 35-40. Beyreuther BK, Freitag J, Heers C, Krebsfänger N, Scharfenecker U, Stöhr T. Lacosamide: A Review of Preclinical Properties. CNS Drug Reviews 2007; Vol.13, No. 1, pp.21-42. Biton V, Rosenfeld WE, Whitesides J, Fountain NB, Vaiciene N, Rudd GD. Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures. Epilepsia 2008; 49(3):418-424. Chung S, Sperling MR, Biton V, Krauss G, Hebert D, Rudd GD, Doty P. Lacosamide as adjunctive therapy for partial-onset seizures: A randomized controlled trial. Epilepsia 2010, 51(6):958–967. (Study 2) Errington AC, Stöhr T, Heers C, Lees G. The investigational anticonvulsant LCM selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol 2008; 73:157-169. Halász P, Kälviäinen R, Mazurikiewicz-Beldzińska M, Rosenow F, Doty P, Hebert D, Sullivan T. Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. Epilepsia 2009; 50(3): 443-453. (Study 3)

IMPORTANT: PLEASE READ


PART III: CONSUMER INFORMATION

PrVIMPAT® (lacosamide)

This leaflet is part III of a three-part "Product Monograph" published when VIMPAT was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about VIMPAT. Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

What the medication is used for: VIMPAT is a prescription medicine used to treat partial-onset seizures when taken together with other seizure medicines in adults 18 years and older. What it does: VIMPAT works in the brain to block the spread of seizure activity. The precise way that VIMPAT works to treat partial-onset seizures is unknown. When it should not be used: Do not take VIMPAT if: you are allergic to lacosamide or any of the other ingredients

in VIMPAT listed in the “nonmedicinal ingredients” section below.

you suffer or have suffered in the past from a certain type of heart rhythm disorder (second or third degree AV block)

What the medicinal ingredient is: Lacosamide What the nonmedicinal ingredients are: VIMPAT Tablets nonmedicinal ingredients: colloidal silicon dioxide, crospovidone, hydroxypropylcellulose, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide and additional agents listed below. 50 mg tablets: red iron oxide, black iron oxide, FD&C Blue #2/indigo carmine aluminum lake 100 mg tablets: yellow iron oxide 150 mg tablets: yellow iron oxide, red iron oxide, black iron oxide 200 mg tablets: FD&C Blue #2/indigo carmine aluminum lake VIMPAT Solution for injection nonmedicinal ingredients: hydrochloric acid, sodium chloride and water for injection. What dosage forms it comes in: Film-coated tablets: 50 mg, 100 mg, 150 mg and 200 mg Solution for injection: 10 mg/mL

WARNINGS AND PRECAUTIONS

VIMPAT may cause dizziness and poor coordination which could

increase the risk of accidental injury or a fall. Therefore, you should be careful until you are used to the effects this medicine might have. Do not drive, operate complex machinery, or engage in other hazardous activities until you know how VIMPAT affects you. Ask your doctor when it is okay to do these activities. VIMPAT may cause double vision and blurred vision. If you experience visual disturbances while taking VIMPAT, notify your doctor. A small number of people being treated with anti-epileptics such as VIMPAT have had thoughts of harming or killing themselves. If at any time you have these thoughts, immediately contact your doctor. BEFORE you use VIMPAT talk to your doctor or pharmacist if: you have any health problems, including ones you have had

in the past; you have kidney or liver disease you are taking any medication, including ones you can get

without a prescription; you are taking any medicine which can cause an abnormality

on the ECG (electrocardiogram) called increased PR interval or heart block, for example medicines used to treat certain types of irregular heart beat or heart failure. If you are not sure that the medicines you are taking could have this effect, discuss this with your doctor (e.g. carbamazepine, pregabalin, lamotrigine, beta-blockers, class I antiarrhythmic drugs, etc.)

patients with pacemaker problems you suffer from a severe heart disease such as heart rhythm

disorder, heart failure or heart attack; you are pregnant or plan to become pregnant. It is not

known if VIMPAT may harm your unborn baby. You and your doctor will have to decide if VIMPAT is right for you while you are pregnant. If you use VIMPAT while you are pregnant, ask your healthcare provider about joining the North American Antiepileptic Drug Pregnancy Registry by calling (888) 233-2334 (toll free). Women who are pregnant and planning to take VIMPAT should call the pregnancy registry to enable collection of valuable data about VIMPAT use in pregnancy. Information on the registry can also be found at the following website: http://www.aedpregnancyregistry.org/ ;

you are breastfeeding. It is not known if VIMPAT passes into breast milk and if it can harm your baby. You and your doctor should decide whether you should take VIMPAT or breastfeed, but not both.

INTERACTIONS WITH THIS MEDICATION

Tell your doctor about all the medicines you take including prescription or non-prescription medicines, vitamins or herbal



supplements. VIMPAT and other medicines may affect each other. Especially tell your doctor if you take: any medicines that make you sleepy or dizzy any medications to treat a heart condition carbamazepine, pregabalin, lamotrigine, beta-blockers, class I

antiarrhythmic drugs, etc.

PROPER USE OF THIS MEDICATION

Usual dose: VIMPAT must be taken twice a day, once in the morning and once in the evening, at about the same time each day. The treatment with VIMPAT usually starts with a dose of 100 mg daily given half (50 mg) in the morning and half (50 mg) in the evening. After one week your dose may be increased. The daily maintenance dose is between 200 mg and 400 mg. Your doctor may use a different dose if you have problems with your kidneys. If your doctor decides to stop your treatment with VIMPAT, he/she will decrease the dose step by step. This is to prevent your symptoms from coming back again or becoming worse. Do not stop taking VIMPAT or any other seizure medicine unless your healthcare provider told you to. Stopping a seizure medicine all at once can cause seizures that will not stop (status epilepticus), a very serious problem. Tell your healthcare provider if your seizures get worse or if you have any new types of seizures. VIMPAT film-coated tablets: VIMPAT may be taken with or without food. Swallow the tablets whole with plenty of water. Do not chew or crush tablets. VIMPAT Solution for injection: The solution for injection is an alternative form of treatment for a short period of time, up to 5 days, when VIMPAT can't be taken by mouth. It will be administered as an injection into a vein (intravenously) by a healthcare professional. Remember: This medicine has been prescribed for you. Do not give it to anybody else. Overdose:

In case of drug overdose, contact a health care practitioner, hospital emergency department or regional Poison Control Centre immediately, even if there are no symptoms. Make sure you take your medicine with you to show the doctor.

Missed Dose: If you miss a dose by a few hours, take it as soon as you remember. If it is close to your next dose, take VIMPAT at your

next regular time. Do not take two doses at the same time to make up for the missed dose.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

The most common side effects associated with the use of VIMPAT are: dizziness, poor coordination headache nausea, vomiting, fatigue blurred vision, double vision Tell your doctor about any side effect that bothers you or that does not go away.

SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect Talk with your doctor or

pharmacist

Seek Emergency

Medical Attention

Only if severe

In all cases

Uncommon Thoughts of suicide or hurting yourself

√

Allergic reaction (symptoms include swelling in the mouth, tongue, face and throat, itching, rash)

√

Cardiac arrhythmias; potential symptoms: irregular pulse, slow pulse, rapid pulse, palpitations, shortness of breath

√



SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN AND WHAT TO DO ABOUT THEM

Symptom / effect Talk with your doctor or

pharmacist

Seek Emergency

Medical

Rare Allergic reactions that typically present with fever, rash and swollen lymph nodes, and may be associated with signs and symptoms involving other organs, e.g. liver.

√

This is not a complete list of side effects. For any unexpected effects while taking VIMPAT, contact your doctor or pharmacist.

HOW TO STORE IT

Store VIMPAT at room temperature, 15 to 30°C. Keep VIMPAT and all medicines out of the reach and sight of

children.

REPORTING SUSPECTED SIDE EFFECTS You can report any suspected adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following 3 ways: • Report online at www.healthcanada.gc.ca/medeffect • Call toll-free at 1-866-234-2345 • Complete a Canada Vigilance Reporting Form and: - Fax toll-free to 1-866-678-6789, or - Mail to: Canada Vigilance Program Health Canada Postal Locator 0701D Ottawa, ON K1A 0K9 Postage paid labels, Canada Vigilance Reporting Form and the adverse reaction reporting guidelines are available on the MedEffect™ Canada Web site at www.healthcanada.gc.ca/medeffect. NOTE: Should you require information related to the management of side effects, contact your health professional. The Canada Vigilance Program does not provide medical advice.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be provided by contacting the sponsor,

UCB Canada Inc. at: 1-866-709-8444

This leaflet was prepared by UCB Canada Inc. Last revised: October 06, 2011

® Registered trademark used under license from Harris FRC Corporation

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PRODUCT MONOGRAPH - Home | UCB (lacosamide) Page 1 of 36 PRODUCT MONOGRAPH PrVIMPAT® lacosamide 50 mg, 100 mg, 150 mg and 200 mg film-coated tablets and 10 mg/mL solution for injection